The long-term goal of this proposal is to understand how viral respiratory infections lead to asthma. In that context, we have proposed that airway epithelial cells (the viral host cells) may be specially programmed for normal immune defense and abnormally programmed in asthma. The current proposal is based on new findings related to regulation of airway epithelial cell death/desquamation and proliferation/renewal in the context of viral infections relevant to asthma. Thus, in studies of isolated cells, we found distinct behavior for respiratory syncytial virus (RSV)- (and surface receptor-) inducible death that came with mitochondrial dysfunction (likely mediated by BCL-2 family proteins) even without activation of apoptosis-related endoproteases (caspases). In these studies, RSV-inducible cell death was also coined to a proliferative response that was marked by a subpopulation of hyperproliferating airway epithelial cells. The pathophysiologic impact of these findings became evident in studies of mice, when we found that paramyxoviral infection (using Sendai virus) caused epithelial cell death during the acute tracheobronchitis, but then led to unchecked airway epithelial proliferation/hyperplasia with striking remodeling/thickening of the airway epithelium and concomitant bronchial hyperreactivity. The airway epithelial remodeling and hyperreactivity persisted for at least a year after the acute tracheobronchitis was resolved, and was marked by increased epithelial expression of the cell survival factor BCL-2. To our knowledge, these models form the initial basis for a link between primary paramyxovirus infection and the subsequent development of long-lasting airway epithelial remodeling and hyperreactivity. In this setting, we propose that virus-inducible cell death depends on acute mitochondrial events (with activation of pro-apoptotic BCL-2 family proteins) whereas hyperplasia may depend on prolonged cell survival (driven by chronic overexpression of anti-apoptotic BCL-2) in combination with cell proliferation. Proliferating cells must move from G to S phase of the cell cycle, and this step requires inactivation of retinoblastoma (Rb) or Rb-related proteins. We suggest that viral replication flips a molecular switch in the BCL-2-regulated cell death and Rb regulated proliferation pathways that may last far beyond the initial acute infection and in this model appears to last for the life of the animal. We now aim to further define the molecular basis for the distinct death and proliferative capacities of airway epithelial cells exhibited in response to paramyxoviral infection using a combined in vitro and in vivo approach. Accordingly, we propose to: (I) Define the molecular components that mediate RSV-inducible death and proliferation in primary-culture human airway epithelial cells focusing on specific determinants of cell survival (i.e., BCL-2 family proteins) and cell cycle control (i.e., Rb- and Rb-related proteins); and (II) Determine the role of these same cell survival and cell cycle regulatory factors in epithelial remodeling and airway hyperreactivity in a mouse model of paramyxoviral tracheobronchitis using wild-type and genetically-modified mice.